Cancer is a major cause of morbidity and mortality in the United States. Treatment of cancer generally includes chemotherapy, radiation therapy and surgery. Unfortunately, most cancers cannot be cured using chemotherapy because tumor cells tend to develop resistance to several chemotherapeutic agents over time. These cancers are referred to as "multidrug-resistant cancers" (MDR).
Overexpression of a number of proteins has been found to be associated with MDR cells lines, including P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). These proteins appear to mediate drug resistance by acting as cytotoxic drug efflux pumps. However, many MDR cancer cell lines are known which are not associated with overexpression of either P-glycoprotein or multidrug resistance-associated protein.
More recently, a protein has been described that is overexpressed in MDR tumor cell lines which do not overexpress either P-glycoprotein or multidrug resistance-associated protein. This protein was originally named Lung Resistance-related Protein (LRP), referring to the cell line in which it was originally identified. However, once the cDNA for Lung Resistance-related Protein was isolated and the corresponding protein sequence elucidated, it was found that Lung Resistance-related Protein was human major vault protein, a previously known protein.
Vaults are large, barrel-shaped, multi-subunit, cytoplasmic, ribonucleoprotein organelles found in virtually all higher organisms and in most normal tissues. Mammalian vaults consist of three proteins having molecular weights of approximately 210, 193 and 104, and a small RNA in the relative molar ratios of 1:1:24:4 in rats. The most abundant of these, the 104 kDa protein, is termed major vault protein (MVP) and corresponds to the Lung Resistance-related Protein. The minor vault protein p193, however, has not yet been characterized.
Therefore, there remains a need for chemotherapeutic agents that will target multidrug-resistant cancers. Further, there remains a need to characterize the minor vault protein p193.